This invention relates to a process for the purification of crude chenodeoxycholic acid.
Chenodeoxycholic acid is useful in human medicine for the treatment of cholelithiasis, due to its gallstone-dissolving activity.
Chenodeoxycholic acid is generally produced from a natural starting material by esterifying the cholic acid in the cholic acid fraction of bile. The 3- and 7-hydroxy groups are selectively acetylated and the free 12-hydroxy groups is thereafter oxidized to a keto group with chromic acid. The 12-keto compound is then heated in the presence of hydrazine hydrate and potassium hydroxide in ethylene glycol over a prolonged period of time to temperatures of around 200.degree.C.
The crude chenodeoxycholic acid contains, due to its method manufacture, a number of by-products which can be separated only with great difficulties. Also, the thus-obtained product has a rather glass-like property and can by crystallized only with great difficulties. Reprecipitation or recrystallization of the crude chenodeoxycholic acid in a suitable solvent has practically no purifying effect at all.
It is known from German Unexamined Laid-Open Application DOS No. 2,302,774 that purification is possible by treating a methanolic solution of the crude chenodeoxycholic acid with a calcium salt or a strontium salt and then rendering the product alkaline, thus precipitating the calcium or strontium salt of chenodeoxycholic acid. After separation, the product is then acidified, and the purified chenodeoxycholic acid is extracted. The purity of the thus-obtained chenodeoxycholic acid is established by chromatography. The melting point which is a criterion of purity is not mentioned.
For the treatment of cholelithiasis, however, chenodeoxycholic acid of very high purity is required. Impurities can lead to undesired side effects, especially since chenodeoxycholic acid, according to previous experience, must be administered in relatively large dosages and over a rather long period of time.
It is an object of the present invention to provide a method for the purification of crude chenodeoxycholic acid wherein a crystalline chenodeoxycholic acid of both high purity and with a high melting point is obtained.